The goal of this project is to investigate experimentally the physical basis of the stability of folded, native conformation of proteins and obtain quantitative information on the energetics of interactions determining this conformation. The lack of this information appears to be the main obstacle in understanding the principles of protein architecture and functioning, and, consequently, in designing the new proteins with the required structure and stability. The energetics of interactions in protein will be estimated by microcalorimetric studies of the processes of (a) unfolding/refolding of proteins with known three-dimensional structure and their mutant forms, and (b) transferring into water the low molecular substances modelling various groups in proteins. These experiments will be carried out in a broad temperature range and the use of new, precise reaction and scanning microcalorimetric techniques will enable us to determine the thermodynamic functions specifying these processes with much higher accuracy and completeness than has been possible before. Analyzing these functions, and especially their temperature dependencies, on the base of structural information on the folded and unfolded conformations, we can evaluate the contribution of hydration effects and intramolecular bonding in stabilization of the native protein structure and clarify, particularly, the mechanism of hydrophobic interactions.